Higher CR Rates in CLL When Rituximab Added to FC Therapy

NEW ORLEANS—The addition of rituximab (Rituxan)—a monoclonal antibody directed against the CD20 antigen—to a fludarabine/cyclophosphamide (FC) regimen for the treatment of chronic lymphocytic leukemia (CLL) led to a surprisingly improved complete remission rate with no increase in toxic effects, Michael J. Keating, MD, said at a poster session at the 36th Annual Meeting of the American Society of Clinical Oncology.

“As we’ve been going through the treatments for CLL, we’ve built on the observation that fludarabine is the most active single drug we have,” said Dr. Keating, of M.D. Anderson Cancer Center. The question tested in this study was whether an even more active treatment regimen could be developed with the addition of rituximab.

The investigation was inspired by previous research showing that rituximab indeed has activity in lymphatic cancer at high doses. The drug had been believed to be ineffective for CLL because it tends to be cleared from the body quickly in patients with lymphocytic lymphoma, Dr. Keating said.

“Previously, our dose-escalation study found that at doses of 500 mg/m² or lower, the response rate was 22%, and when we got up to 850 to 1,000 mg/m², the response rate rose to 53%. When we went to 1,500 to 2,250 mg/m², the response rate went up above 70%,” he said.

Research showed the agent to be active with a distinct mechanism. “There is in vitro evidence in some cell lines showing that rituximab creates a synergism with chemotherapy that enhances the cell kill,” he commented.

Based on that experience, the investigators launched the current study to investigate whether adding rituximab to an FC regimen would increase the complete response rate to higher than 50% without increasing morbidity.

The study enrolled 35 patients with either advanced RAI stage III-IV disease (16 patients), or progressive RAI stage I-II disease (19 patients). The median age was 54 years, and most patients (25) were male. Those with stage I-II disease met criteria for active disease (symptoms of progressive lymphocytosis, worsening anemia or thrombocytopenia, weight loss, fatigue, or fever).

Rituximab was given at a dose of 375 mg/m² on day 1 of course 1, and at 500 mg/m² for courses 2 to 6. Fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² were given on days 2 to 4 of course 1, and on days 1 to 3 of courses 2 to 6.

Dr. Keating reported that all 35 patients completed three courses. Twelve of these patients (34%) had a complete response, 11 had a partial response (31%), and 10 (29%) had a nodular partial response for a total response rate of 94%. Two patients had no response.

Fifteen patients had completed all six cycles of treatment at the time of the presentation, 9 of whom (60%) were in complete remission. Only 1 of the 15 patients had no response. Another 13% (2 patients) had a partial remission, and 20% (3 patients) had a nodular partial response, for a total response rate of 93%. Five of nine patients evaluated by PCR were PCR negative for Ig heavy chain rearrangement in the marrow.

Dr. Keating said that four patients (11%) experienced grade 3-4 toxicity while receiving the first dose of rituximab. Symptoms included fever, chills, hypotension, and dyspnea.

Rates of grade 3-4 neutropenia in patients receiving the FC plus rituximab regimen were comparable to the rates seen in patients getting FC alone, at about 20% to 25%, and should be monitored, he said.

Three patients in the study experienced tumor lysis syndrome, an adverse event not expected in treatment with FC alone.

“With fludarabine by itself as front-line treatment of CLL, there will be a 30% complete remission rate. With FC, there will be a 35% complete remission rate,” Dr. Keating said, noting that FC plus rituximab offers a significant improvement, based on this small study.

Dr. Keating, in addition, was enthusiastic about the quality of the remissions achieved with the combination. CLL cells, he explained, co-express CD5 and CD19. “In the past, we’ve been satisfied with getting CD5 and CD19 levels of about 5% to 10% after treatment,” he said. In this study, however, CD5 and CD19 levels were less than 1% in most patients.

“We’ve never seen remissions as complete as that before, and there doesn’t seem to be any increase in toxicity with the addition of rituximab, compared with FC alone,” Dr. Keating said.